The tumor microenvironment (TME) plays an important role in the development, persistence and disease progression in cancer. Lymphoid malignancies, in particular B-cell malignancies residing in the bone marrow, are an example of malignancies depending on the microenvironment. These malignancies are serious and often fatal. Although significant advances have been made in our understanding of the biology of these cancers, most remain incurable and clearly, new therapies are needed. Because the TME plays an integral role in malignant B-cell functions, it is difficult to dissociate it from cancer ells. There is compelling evidence to suggest that the crosstalk between malignant B cells and bone marrow stromal cells favors disease progression. Therefore, disrupting the crosstalk between cancer cells and stromal cells is an attractive therapeutic strategy for the treatment of these lymphoid malignancies. In addition, combining therapies that target the TME and malignant cells will inhibit the crosstalk between these two compartments and lead to improved survival of cancer patients. Therefore, a better understanding of the signaling mechanisms modulating the TME in B-cell malignancies is necessary for the development of novel targeted therapies for these devastating diseases and the appropriate choice of therapy must be derived from a detailed knowledge of the signaling network controlling this cellular crosstalk. Cytokines play a key role in regulating the crosstalk between malignant cells and non-malignant cells in the TME. Although this phenomenon is well established, the molecular mechanisms regulating this cellular event in the TME remain elusive. We identified a novel CCR3-PI3K-AKT-GLI2 pathway in stromal cells that is initiated by the cytokine CCL5, leading to increased IL-6 secretion by stromal cells. IL-6 secretion from the TME, in turn, promotes immunoglobulin M (IgM) secretion by malignant B cells. Therefore, disrupting the CCR3-PI3K-AKT-GLI2-IL-6 signaling pathway in the TME alone or in combination with rituximab therapy may provide therapeutic efficacy by targeting 2 components of malignant phenotype; the malignant cells (Rituximab therapy) and stromal cell signaling (CCR3 and/or IL-6 blockade). We have recently identified novel target molecules of CCR3-PI3K-AKT-GLI2 pathway including CCL2, CCL7 and CD40L. A better understanding of the molecular mechanisms regulated by these cytokines may facilitate the development of novel therapies. In this application we propose to expand on these findings and address the CENTRAL HYPOTHESIS that the CCR3-PI3K-AKT-GLI2 pathway contributes to the maintenance of an active TME in B-cell malignancies and thus represents a viable therapeutic target. To address this hypothesis, we propose two specific aims: AIM 1: To determine the translational implications of the combined targeting of CCR3 and/or IL-6 in combination with rituximab therapy in a B-cell malignancy mouse model and AIM 2: To characterize the role of CCR3-PI3K- AKT-GLI2 axis in the TME.